ABSTRACT Proprotein convertase subtilisin/kexin type 9 (PCSK9) is new drug target to lower low-density lipoprotein cholesterol (LDL) and prevent coronary heart disease (CHD). PCSK9 inhibitor drugs lower LDL levels markedly ? to below 25 mg/dL in 37% of patients ? and show promise for CHD prevention. However, PCSK9 is widely expressed in many tissues and has biological effects beyond lowering LDL. For example, PCSK9 decreases the clearance of lipopolysaccharide (LPS); reduced PCSK9 function is associated with improved survival from sepsis in animal models and humans. Additionally, PCSK9 has effects on bone, pancreas, brain and nerve tissues, among others. The benefits and risks from inhibiting the pleiotropic effects of PCSK9 and from long-term exposure to extremely low LDL levels are not known, but clinical trials have already raised concerns about effects on cognitive function. Thus, the recent approval of the first of many PCSK9 inhibitors in development has exposed critical knowledge gaps: we do not know the potential long-term beneficial and deleterious effects of 1) PCSK9 inhibition, or 2) extremely low LDL levels. Traditional post-marketing drug- safety approaches to these questions would require decades of clinical studies to determine these long-term effects. We hypothesize that the unknown beneficial and deleterious effects of long-term PCSK9 inhibition can be defined by studying individuals with genetically determined (and therefore lifetime exposure) variation in PCSK9 activity. Similarly, the unknown risks and benefits of very low LDL levels can be defined by studying individuals who have extremely low LDL levels unrelated to drug exposure. We will use BioVU, a database with in depth genotyping linked to the de-identified electronic EHR in > 100,000 individuals at Vanderbilt to define the potential risks and benefits of both PCSK9 inhibition and extremely low LDL levels. In Aim 1 we will test the hypothesis that individuals with genetically determined low PCSK9 function have a lower risk of progressing from infection to severe sepsis and septic shock. In Aim 2 we will use a combination of unbiased phenotype identification (phenome-wide association scan or PheWAS) followed by rigorous validation of identified phenotypes to test the hypothesis that PCSK9 variants associated with reduced function are associated with clinical outcomes other than lower LDL. Aim 3 will use the same approach as Aim 2 to define the clinical outcomes associated with very low LDL concentrations in the entire de-identified set of electronic health records at Vanderbilt University Medical Center consisting of >2,500,000 patients of whom >246,000 have had an LDL level measured. This proposal uses novel approaches to rapidly provide critical information about the clinical consequences of both long-term PCSK9 inhibition and long-term low LDL levels that would otherwise not be obtained without many years of patient exposure to PCSK9 drugs.